Retrospective review of the use of daptomycin for diabetic foot infections.

The increase in antibiotic resistance has led to a search for alternative treatments for diabetic foot infections. This retrospective review outlines the clinical outcomes reported for a lipopetide for these infections.

Safety and efficacy of daptomycin in the treatment of osteomyelitis: results from the CORE Registry.

Antibiotic safety is a major determinant in osteomyelitis therapy. Limited data is available describing the long-term safety and efficacy of daptomycin. the safety population was drawn from CORE 2005 and 2006, a retrospective, observational, multicenter study. Clinically evaluable patients received >3 days of daptomycin appropriately adjusted for renal function. three hundred twenty-seven patients were evaluated for safety; 188 (57%) >or=6 mg/kg, 139 (43%) <6 mg/kg. Thirty-one (10%) patients experienced adverse events possibly related to daptomycin and the incidence was similar regardless of dose. No difference was observed in the rate of creatine phosphokinase elevations by dose. A trend toward higher improved rates was noted in patients receiving a final dose of >or=6mg/kg (96% vs. 90%, P=0.08). Daptomycin appeared well-tolerated at doses of 6 mg per kg or greater which were associated with greater clinical improvement. These results require verification via a prospective clinical trial.

Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials.

Metronidazole, the prototype nitroimidazole antimicrobial, was originally introduced to treat Trichomonas vaginalis, but is now used for the treatment of anaerobic and protozoal infections. The nitroimidazoles are bactericidal through toxic metabolites which cause DNA strand breakage. Resistance, both clinical and microbiological, has been described only rarely. Metronidazole given orally is absorbed almost completely, with bioavailability > 90% for tablets; absorption is unaffected by infection. Rectal and intravaginal absorption are 67 to 82%, and 20 to 56%, of the dose, respectively. Metronidazole is distributed widely and has low protein binding (< 20%). The volume of distribution at steady state in adults is 0.51 to 1.1 L/kg. Metronidazole reaches 60 to 100% of plasma concentrations in most tissues studied, including the central nervous system, but does not reach high concentrations in placental tissue. Metronidazole is extensively metabolised by the liver to 5 metabolites. The hydroxy metabolite has biological activity of 30 to 65% and a longer elimination half-life than the parent compound. The majority of metronidazole and its metabolites are excreted in urine and faeces, with less than 12% excreted unchanged in urine. The pharmacokinetics of metronidazole are unaffected by acute or chronic renal failure, haemodialysis, continuous ambulatory peritoneal dialysis, age, pregnancy or enteric disease. Renal dysfunction reduces the elimination of metronidazole metabolites; however, no toxicity has been documented and dosage alterations are unnecessary. Liver disease leads to a decreased clearance of metronidazole and dosage reduction is recommended. Recent pharmacodynamic studies of metronidazole have demonstrated activity for 12 to 24 hours after administration of metronidazole 1 g. The post-antibiotic effect of metronidazole extends beyond 3 hours after the concentration falls below the minimum inhibitory concentration (MIC). The concentration-dependent bactericidal activity, prolonged half-life and sustained activity in plasma support the clinical evaluation of higher doses of metronidazole given less frequently. Metronidazole-containing regimens for Helicobacter pylori in combination with proton pump inhibitors demonstrate higher success rates than antimicrobial regimens alone. The pharmacokinetics of metronidazole in gastric fluid appear contradictory to these results, since omeprazole reduces peak drug concentration and area under the concentration-time curve for metronidazole and its hydroxy metabolite; however, concentrations remain above the MIC. Other members of this class include tinidazole, ornidazole and secnidazole. They are also well absorbed and distributed after oral administration. Their only distinguishing features are prolonged half-lives compared with metronidazole. The choice of nitroimidazole may be influenced by the longer administration intervals possible with other members of this class; however, metronidazole remains the predominant antimicrobial for anaerobic and protozoal infections.

Relative bioavailability of atovaquone suspension when administered with an enteral nutrition supplement.

OBJECTIVE: To compare the relative bioavailability of a single atovaquone 750 mg suspension oral dose when administered in the fasting state, after a normal breakfast, and after an enteral nutrition supplement. DESIGN: Ten healthy volunteers received a single dose of atovaquone suspension 750 mg/5 mL while fasting. At 2-week intervals, the subjects were then randomized in a crossover design to receive the atovaquone dose within 1 hour of consuming a normal breakfast (fat content 21 g) and 16 oz. of Sustacal Plus (fat content 28 g). Blood samples were collected at seven time points after each atovaquone dose. HPLC was used to determine the atovaquone concentrations in plasma. RESULTS: Administering atovaquone suspension with either a normal breakfast or an enteral nutrition supplement, such as Sustacal Plus, significantly increased the oral relative bioavailability. The mean AUC0-24 after the fasting dose was 43.4 micrograms.h/mL. The mean AUC0-24 values with breakfast (103.8 micrograms.h/mL) and Sustacal Plus (118.8 micrograms.h/mL) were significantly greater compared with fasting (p < 0.0001). CONCLUSIONS: This study has shown that the new atovaquone oral suspension also has significantly greater bioavailability when administered after food or a nutrition supplement that has a moderate fat content. Patients who require atovaquone therapy can use Sustacal Plus without risk of reduced absorption.

Pharmacodynamics of ampicillin-sulbactam in an in vitro infection model against Escherichia coli strains with various levels of resistance.

The activity of ampicillin-sulbactam against beta-lactamase-producing Escherichia coli has been questioned. Therefore, in this study, the killing activity of ampicillin-sulbactam was investigated in an in vitro infection model which simulates human pharmacokinetics. One ampicillin-sensitive strain (E. coli ATCC 25922, ampicillin-sulbactam MIC = 4/2 microg/ml) and three ampicillin-resistant TEM-1-producing strains with various levels of ampicillin-sulbactam resistance (EC11, MIC = 4/2 microg/ml; TIM2, MIC = 12/6 microg/ml; and GB85, MIC > 128/64 microg/ml) were studied. The E. coli strains were exposed to ampicillin-sulbactam at a starting inoculum of 6 to 7 log10 CFU/ml. Ampicillin-sulbactam was infused over 30 min to simulate doses of 3 and 1.5 g every 6 h for 24 h. The 3-g ampicillin-sulbactam dose was bactericidal against E. coli ATCC 25922, EC11, and TIM2. The 1.5-g dose displayed bactericidal activity against ATCC 25922 and EC11 similar to that of the higher dose but failed to kill TIM2 due to inadequate time above the MIC and increased MICs over 24 h. GB85 was highly resistant and grew similarly to controls. Despite an MIC at 10(7) CFU/ml indicating resistance (20/10 microg/ml), TIM2 was killed by the 3-g dose of ampicillin-sulbactam. Current MIC breakpoints may not adequately portray the activity of ampicillin-sulbactam, considering both the activity in in vitro infection models and clinical data.

Metronidazole. A therapeutic review and update.

The nitroimidazole antibiotic metronidazole has a limited spectrum of activity that encompasses various protozoans and most Gram-negative and Gram-positive anaerobic bacteria. Metronidazole has activity against protozoans like Entamoeba histolytica, Giardia lamblia and Trichomonas vaginalis, for which the drug was first approved as an effective treatment. Anaerobic bacteria which are typically sensitive are primarily Gram-negative anaerobes belonging to the Bacteroides and Fusobacterium spp. Gram-positive anaerobes such as peptostreptococci and Clostridia spp. are likely to test sensitive to metronidazole, but resistant isolates are probably encountered with greater frequency than with the Gram-negative anaerobes. Gardnerella vaginalis is a pleomorphic Gram-variable bacterial bacillus that is also susceptible to metronidazole. Helicobacter pylori has been strongly associated with gastritis and duodenal ulcers. Classic regimens for eradicating this pathogen have included metronidazole, usually with acid suppression medication plus bismuth and amoxicillin. The activity of metronidazole against anaerobic bowel flora has been used for prophylaxis and treatment of patients with Crohn's disease who might develop an infectious complication. Treatment of Clostridium difficile-induced pseudomembraneous colitis has usually been with oral metronidazole or vancomycin, but the lower cost and similar efficacy of metronidazole, coupled with the increased concern about imprudent use of vancomycin leading to increased resistance in enterococci, have made metronidazole the preferred agent here. Metronidazole has played an important role in anaerobic-related infections. Advantages to using metronidazole are the percentage of sensitive Gram-negative anaerobes, its availability as oral and intravenous dosage forms, its rapid bacterial killing, its good tissue penetration, its considerably lower chance of inducing C. difficile colitis, and expense. Metronidazole has notable effectiveness in treating anaerobic brain abscesses. Metronidazole is a cost-effective agent due to its low acquisition cost, its pharmacokinetics and pharmacodynamics, an acceptable adverse effect profile, and its undiminished antimicrobial activity. While its role as part of a therapeutic regimen for treating mixed aerobic/anaerobic infections has been reduced by newer, more expensive combination therapies, these new combinations have not been shown to have any therapeutic advantage over metronidazole. Although the use of metronidazole on a global scale has been curtailed by newer agents for various infections, metronidazole still has a role for these and other therapeutic uses. Many clinicians still consider metronidazole to be the 'gold standard' antibiotic against which all other antibiotics with anaerobic activity should be compared.

Low pharmacist counseling rates in the Kansas City, Missouri, metropolitan area.

OBJECTIVE: To quantify the percentage of patients counseled by community-based pharmacists. METHODS: Phase I consisted of a 15-minute observational period of pharmacist counseling in 50 randomly selected pharmacies in the Kansas City, MO, area. In phase II, a survey was mailed to the same pharmacies to obtain policies, self-reported rates of counseling, baseline workload, and personnel information, as well as perceived communication barriers. RESULTS: Forty-six of 50 pharmacies were observed in phase I after excluding 10 ineligible pharmacies and adding 6 replacement pharmacies. Pharmacists provided counseling in only 14 of the 46 pharmacies (30%). Nineteen percent (20/106) of all patients received pharmacist-initiated counseling. Pharmacists in independent pharmacies were observed counseling a significantly higher percentage of patients than were pharmacists in chain pharmacies (44% vs. 11%; p = 0.014). Technicians were observed counseling 5 patients in chain pharmacies. Detailed verbal counseling, defined as four or more of a group of major counseling components, was provided to only 8 of the 20 patients who were counseled by a pharmacist (40%; 8% of all patients). In phase II, 31 of 51 surveys (61%) were returned. During the requested survey time period, pharmacies estimated that approximately five prescriptions were filled every 15 minutes, 51.5% of which were new. Pharmacists in chain pharmacies reported dispensing greater numbers of prescriptions than did pharmacists in independent pharmacies. These data and the reported counseling rates indicated that 50% of all patient prescriptions should be counseled. This is a higher rate than actually observed. All pharmacies reported that pharmacists completed the counseling; however, 10% of the respondents reported that technicians also counseled patients. Contrary to the findings in phase I, slightly more than 50% of the pharmacists reported using detailed verbal counseling. CONCLUSIONS: The overall observed rate of counseling in community pharmacies is low. In the Kansas City area, independent pharmacists counsel a greater than average percentage of their patients. Even if the national counseling rate is double what was observed, millions of patients are leaving pharmacies without the benefit of pharmacotherapeutic guidance. If pharmacists are slow to meet these challenges, other service providers will relieve pharmacists of that responsibility.

Influence of antibiotic and E5 monoclonal immunoglobulin M interactions on endotoxin release from Escherichia coli and Pseudomonas aeruginosa.

Recent controversy surrounding the activity of monoclonal antibodies against endotoxin highlights the necessity of identifying all factors associated with increased mortality, one of which is endotoxin concentrations. Antibiotics may induce different patterns of endotoxin release. We compared the release of free endotoxin (in endotoxin units per milliliter) over 6 h and changes in numbers of CFU of exponentially growing Escherichia coli and Pseudomonas aeruginosa (10(6) to 10(7) CFU/ml) cultured in chemically defined endotoxin-free broth combined with pooled human serum and/or 10 micrograms of E5 immunoglobulin M monoclonal antibody per ml. MICs and MBCs were tested in each medium at the same inoculum. The inoculum was exposed to antibiotics at a single fixed multiple of the MIC for each medium (range, two to eight times the MIC). E5 antibody had no effect on MICs, MBCs, bactericidal activity, or endotoxin release. In the presence of 50% serum, amikacin, ceftazidime, imipenem, and ofloxacin each killed equivalent amounts of E. coli over 6 h; however, ceftazidime induced the highest release of endotoxin. Amikacin and ofloxacin produced the most favorable ratio of endotoxin release to amount of bacterial killing. In the presence of 50% serum, ceftazidime and imipenem reduced the P. aeruginosa inoculum to the greatest extent over 6 h. Although its bactericidal activity was diminished, ofloxacin caused the lowest release of free endotoxin. Imipenem and ofloxacin showed similar low ratios of endotoxin release to bacterial killing. In summary, antibiotic class, presence of serum, and type of organism influenced bactericidal activity and endotoxin release.

Effect of human serum on killing activity of vancomycin and teicoplanin against Staphylococcus aureus.

STUDY OBJECTIVE: To investigate the effects of pooled human serum (PHS) on the killing activity of vancomycin and teicoplanin against two isolates of Staphylococcus aureus from patients treated for endocarditis. DESIGN: An in vitro assessment of antibiotic susceptibility and killing rates. SETTING: An urban university teaching hospital. PATIENTS: Pooled human serum from patients treated for endocarditis. INTERVENTIONS: Two clinical isolates of Staphylococcus aureus were obtained from patients treated for endocarditis. Media consisted of cation-supplemented Mueller-Hinton broth alone and in 1:1 dilutions with PHS, 2-hour heat-inactivated PHS (HI-PHS), ultrafiltrate (UF), and 2-hour heat-inactivated ultrafiltrate (HI-UF). Heat inactivation of PHS and UF was accomplished by treatment at 56 degrees C for 2 hours. MEASUREMENTS AND MAIN RESULTS: Killing curves with vancomycin and teicoplanin were performed using drug concentrations of 45 micrograms/ml and a starting inoculum of approximately 1 x 10(6) colony-forming units (cfu)/ml. Bactericidal rates (-log cfu/ml/hr) were calculated from the slope of the killing curves over 0-12 hours (mean 3-8 replicates). CONCLUSIONS: The killing activity of vancomycin in PHS and HI-PHS against both isolates was significantly greater than all other media tested (p < 0.0001). Ultrafiltrate tended to reverse this enhancement effect. Addition of PHS or UF did not enhance teicoplanin's killing activity against either isolate. Further investigations in our laboratory will determine if the factor is antibiotic class or organism specific.

Pharmacodynamic effects of extended dosing intervals of imipenem alone and in combination with amikacin against Pseudomonas aeruginosa in an in vitro model.

The pharmacodynamic effects of extended imipenem dosing intervals were studied against two strains of Pseudomonas aeruginosa (ATCC 27853 and an imipenem-resistant mutant, 27853R) in an in vitro model of infection. Imipenem was administered as monotherapy (simulated 1-g bolus every 8 or every 12 h) and in combination with amikacin (7.5-mg/kg bolus every 12 h or a 15-mg/kg bolus once). Monotherapy with imipenem administered every 8 h was equally bactericidal at 24 h compared with regimens combined with amikacin for ATCC 27853. Imipenem administered every 12 h against the sensitive strain and both imipenem monotherapy regimens against the resistant strain demonstrated regrowth at 24 h. Although both amikacin regimens administered as monotherapy resulted in rapid bacterial killing activity with respect to time to a 99.9% reduction in log10 CFU/milliliter, regrowth at 24 h was observed at levels reaching or exceeding the initial inoculum. All combination regimens resulted in no detectable growth by 24 h regardless of dosing interval for either drug or initial susceptibility to imipenem. Results from this study indicate the potential for several novel dosing regimens against P. aeruginosa. Monotherapy with imipenem, 1 g every 8 h, was effective against a sensitive strain of P. aeruginosa. Combination therapy with imipenem and once-daily or twice-daily amikacin resulted in increased killing activity against imipenem-resistant P. aeruginosa. Once-daily or twice-daily amikacin in combination therapy, regardless of P. aeruginosa susceptibility, allowed for extension of imipenem dosing intervals.

Prospective evaluation of red man syndrome in patients receiving vancomycin.

The incidence of red man syndrome (RMS) and its relationship to histamine were investigated in patients receiving vancomycin or an aminoglycoside (control). During the 60-min infusions, patients were observed for signs or symptoms consistent with RMS, including pruritus, erythema, angioedema, and cardiovascular depression. Four blood samples were obtained at 30-min intervals for determination of histamine concentrations. One (3.4%) of 29 vancomycin- and none of 8 aminoglycoside-treated patients had documented RMS. The mean maximum changes in blood pressure and heart rate were not significant and were similar between groups. Increases in histamine concentrations to > 1 ng/mL occurred only in 25% (2/8) of the aminoglycoside patients. Vancomycin induced minimal changes in histamine concentrations despite the occurrence of RMS. From these observations, it appears that RMS is not closely associated with histamine release, and elevated histamine concentrations do not predict RMS. Further investigation is needed to elucidate other mediators of RMS.

Teicoplanin and daptomycin bactericidal activities in the presence of albumin or serum under controlled conditions of pH and ionized calcium.

Teicoplanin and daptomycin bactericidal rates (BRs) were measured from standard kill curves in supplemented Mueller-Hinton broth (B), B with 3 g of albumin per dl (BA), B with 50% pooled human serum (BS), and in broth to simulate free concentrations (BF) under controlled physiologic conditions of pH (7.4) and ionized calcium (1.15 to 1.17 mM) against two clinical Staphylococcus aureus strains. Total concentrations of teicoplanin and daptomycin, respectively, were 45 and 12.5 micrograms/ml in B, BA, and BS and 4.5 and 1.25 micrograms/ml in BF. All BRs are reported as log10 CFU per milliliter per hour. There was a trend for the teicoplanin BR to be inhibited by serum for strain 67 (BR in B was -0.26 +/- 0.08 versus a BR in BS of -0.19 +/- 0.08 [P > 0.05]). The teicoplanin BRs for strain 135 were unaffected by the type of medium used (range, -0.17 to -0.20). For both strains, daptomycin BRs were adversely affected by lower concentrations, albumin, and serum. The BR of daptomycin was significantly faster in B (-4.53 +/- 1.92) (P < 0.05) than it was in BF (-0.58 +/- 0.04), BA (-1.68 +/- 0.28), or BS (-1.02 +/- 0.16) against strain 67. BA and BS resulted in BRs more than twice that in BF (P > 0.05). Against strain 135, daptomycin again produced the highest BR in B; however, the BRs in BF, BA, and BS were almost identical, indicating that only free daptomycin was active. After correcting for the influence of protein binding, pH, and ionized calcium, teicoplanin appeared to be inhibited by serum, and daptomycin demonstrated enhanced BRs against different S. aureus strains in the presence of albumin or serum.

Pharmacodynamics of once-daily amikacin in various combinations with cefepime, aztreonam, and ceftazidime against Pseudomonas aeruginosa in an in vitro infection model.

The pharmacodynamics of once-daily amikacin administered as monotherapy and in combination with aztreonam, ceftazidime, and cefepime against Pseudomonas aeruginosa ATCC 27853 and clinical isolate 16690 (moderately susceptible to ceftazidime) were investigated with an in vitro model of infection over a 24-h period. Monotherapy with aztreonam, ceftazidime, and cefepime and combinations of aztreonam with cefepime or ceftazidime were also studied. MICs and MBCs were determined for viable organisms at 24 h to test for the development of resistance. Once-daily amikacin demonstrated killing activity over the initial 8 h superior to those of all other drugs administered as monotherapy against both strains tested (P < 0.01). Regrowth by 24 h was greatest for the amikacin regimen (P < 0.01) but was apparent for all monotherapy regimens against both strains. No changes in susceptibilities were observed. All combination therapies containing once-daily amikacin achieved 99.9% reductions in log10 CFU/ml by 2.0 h against both strains, with no regrowth of organisms at 24 h. Aztreonam-cefepime and -ceftazidime combinations required approximately 5 to 6 h to achieve a 99.9% reduction in log10 CFU/ml. Although there was no difference in time to the 99.9% kill between the aztreonam-cefepime and -ceftazidime regimens against either strain, the killing activity of these combinations was significantly less than those of regimens containing once-daily amikacin (P < 0.01). Minor differences in the initial susceptibilities of beta-lactams and the monobactam aztreonam against P. aeruginosa may not be important for therapeutic outcomes when used in combination with single-daily aminoglycoside therapy.

In vitro pharmacodynamic effects of concentration, pH, and growth phase on serum bactericidal activities of daptomycin and vancomycin.

Clinical trials with daptomycin were halted in December 1990 because of treatment failures including two resistant Staphylococcus aureus strains. High protein binding of daptomycin (> 90%) and the lower-than-expected concentrations in serum with the dosage regimen of 3 mg/kg of body weight every 12 h may have contributed to these failures. To evaluate the effect that higher concentrations would have on bactericidal activity measured by time-kill curves, peak and trough concentrations were estimated for dosage regimens of 3, 5, and 10 mg/kg every 12 h. MICs, MBCs, and killing curves for daptomycin and vancomycin were performed by using the estimated concentrations with four S. aureus strains obtained from patients who failed daptomycin therapy for endocarditis. MICs and MBCs of daptomycin demonstrated a greater inoculum effect than those of vancomycin; MICs and MBCs of daptomycin increased three- to fourfold, but those of vancomycin increased only one- to twofold when the inoculum was increased from 5 x 10(5) to 5 x 10(7) CFU/ml. No pH-dependent effect on MICs or MBCs was seen. Strenuous experimental conditions were chosen: high inoculums (5 x 10(7) CFU/ml), extremes of pH (6.4, 7.4, and 8), and stationary and exponentially growing organisms; and all experiments completed in the presence of pooled human serum. Daptomycin exhibited concentration-dependent killing and statistically faster kill rates than vancomycin against stationary- or exponential-growth-phase organisms. A pH-dependent decrease in activity with daptomycin was also demonstrated. Daptomycin and vancomycin produced higher kill rates against exponentially growing organisms. A pH-dependent decrease in activity with daptomycin was also demonstrated. Daptomycin and vancomycin produced higher kill rates against exponentially growing organisms. The results indicate that the use of higher dosage regimens with compounds similar to daptomycin may be capable of overcoming the effects of pH, high inoculum, and protein binding.

CI-960, a new fluoroquinolone, for therapy of experimental ciprofloxacin-susceptible and -resistant Staphylococcus aureus endocarditis.

CI-960 is a new fluoroquinolone with enhanced in vitro activity against gram-positive pathogens. The efficacy of the drug was compared with that of vancomycin by using the rabbit model of nafcillin- and ciprofloxacin-susceptible and -resistant Staphylococcus aureus endocarditis. Animals received intravenous therapy with CI-960, 20 mg/kg of body weight every 8 h, or vancomycin, 17.5 mg/kg every 6 h, for 4 days. In a comparison with the effects on untreated controls, both antimicrobial agents effectively cleared bacteremia and significantly reduced bacterial counts in vegetations and tissues of animals infected with any of the test strains. In some cases, the efficacy of CI-960 was superior to that of vancomycin. The therapeutic activity of CI-960 was reduced, but still very good, against ciprofloxacin-resistant strains. One rabbit infected with such a strain and treated with CI-960 was found to harbor a small number of vegetation-associated organisms resistant to the drug at fivefold its original MIC; this was associated with a microbiological, but not a clinical, failure of therapy. We conclude that CI-960 is as effective as vancomycin is in this model of a serious systemic S. aureus infection, including that caused by strains resistant to ciprofloxacin. Increases in CI-960 MICs may develop during therapy of infections caused by strains highly resistant to ciprofloxacin, but they appear unlikely to occur in ciprofloxacin-susceptible strains.

Pharmacokinetics and bactericidal rates of daptomycin and vancomycin in intravenous drug abusers being treated for gram-positive endocarditis and bacteremia.

The pharmacokinetics and bactericidal killing rates (BR) of daptomycin (D) and vancomycin (V) in 12 intravenous drug abusers (6 treated with daptomycin and 6 treated with vancomycin) were evaluated. Pharmacokinetic parameters were determined from multiple serum samples drawn at steady state over a 12-h dosing interval after intravenous infusions of 3 mg of D per kg of body weight and 1,000 mg of V. The BRs were determined from the 1- and 6-h serum samples by using four isolates of Staphylococcus aureus (three methicillin susceptible and one methicillin resistant) obtained from the patients enrolled in the study. Peak serum daptomycin concentrations were lower and volumes of distribution were higher than reported in healthy volunteers. Although not statistically different, D clearance was 22% higher than reported in healthy volunteers. V pharmacokinetics were similar to those reported in previous studies. Daptomycin's BRs, although comparable to those of V in patients' serum, were significantly decreased compared with those found in broth. This may be related to the high degree of protein binding of D (93% versus 50% for V). Conversely, the BRs of V in serum were significantly greater than those in broth. The BRs of D and V in broth were greater when killing curves were performed with test strains in logarithmic versus stationary-phase growth. The ability to kill organisms in stationary phase may be an important factor in determining the performance of an antibiotic in deep-seated infections such as endocarditis.3+

Ofloxacin clinical pharmacokinetics.

Ofloxacin is a new fluoroquinolone with a spectrum of activity similar to other fluoroquinolones with activity which includes Chlamydia trachomatis, Mycobacterium spp., Mycoplasma spp. and Legionella pneumophila. Through its additional mechanisms of action, ofloxacin may be less susceptible to the development of resistance from Staphylococcus aureus commonly seen with currently available fluoroquinolones. The impact of these findings cannot be evaluated without further clinical experience. The pharmacokinetics of ofloxacin are characterised by almost complete bioavailability (95 to 100%), peak serum concentrations in the range of 2 to 3 mg/L after a 400mg oral dose and an average half-life of 5 to 8h. In comparison with other available quinolones, elimination is more highly dependent on renal clearance, which may lead to more frequent dosage adjustments in patients with impaired renal function. Ofloxacin appears less likely to affect the pharmacokinetics of drugs (e.g. theophylline) which commonly interact with fluoroquinolones such as ciprofloxacin and enoxacin. The properties of ofloxacin make it a therapeutic alternative to currently available fluoroquinolones.

Indomethacin for prevention of neonatal intraventricular hemorrhage.

Up to 50 percent of premature infants develop an intracerebral hemorrhage. Intracerebral hemorrhage in neonates occurs most frequently in the periventricular or intraventricular areas. Intravascular, vascular, and extravascular factors influence the development of hemorrhage. Pharmacologic therapies, such as phenobarbital, vitamin K, pancuronium bromide, vitamin E, and indomethacin, have been used in an attempt to prevent intraventricular hemorrhage (IH). Indomethacin inhibits prostaglandin production, which results in cerebral vasoconstriction and reduced cerebral blood flow. Several clinical studies have evaluated the role of indomethacin for the prevention of IH in premature infants. No definitive recommendations can be made regarding indomethacin use for this purpose. However, the two largest studies conducted to date have shown indomethacin to be effective in preventing or limiting the progression of IH. The drug appears to be most effective in reducing low-grade IH. More extensive research is needed to determine the most effective dose, duration, and serum concentration of indomethacin.